Patent EA-004502-B1 (EA)
Title: Pharmaceutical composition of serotonin receptor antagonist and method for preparing the same
Inventor: KOHN RACHEL S
IPC: A61P7/02
Filed: 1999-11-22
Abstract: 1. A method for the production of a pharmaceutical composition comprising the steps of: a) mixing a suitable amount of pharmaceutically active compound of Formula I: or a pharmaceutically acceptable salt thereof with a suitable amount of biodegradable polymer for a sufficient period of time and at suitable temperature and pressure conditions to form a dry mixture of said pharmaceutically active compound and said polymer, wherein said biodegradable polymer has a glass transition temperature (Tc) of less than about 60 degree C; b) subjecting said dry mixture to a suitable shear mixing using a single screw extruder under suitable temperature and pressure conditions for a sufficient period of time such that said polymer softens to form a fluidized medium and said pharmaceutically active compound is sufficiently dissolved to form a solid solution having substantially homogeneously dispersed mixture of said pharmaceutically active compound and said polymer, and said homogeneous mixture is formed into a strand; c) pelletizing said strand; and d) pulverizing said pellets to form sustained release microparticles of said biodegradable polymer and said pharmaceutically active compound, wherein said microparticles are having a size distribution in the range of from about 10 to 200 mum such that said microparticles are suitable for forming an injectable formulation. 2. The method as set forth in claim 1 wherein said pharmaceutically active compound is a 5H2A-receptor antagonist. 3. The method as set forth in claim 1 wherein said polymer is selected from the group consisting of polyester, polyamide, polyanhydrides, polyorthoesters, polycarbonates, poly(phosphoesters), poly(phosphazenes), poly(iminocarbonates), and mixtures thereof. 4. The method as set forth in claim 1 wherein said polymer is selected from the group consisting of polylactide, polyglycolide, polylactide-co-glycolide, polyhydroxybutyrate, polycaprolactone, polytartarate, and mixtures thereof. 5. The method as set forth in claim 1 wherein said polymer is polylactide-co-glycolide. 6. The method as set forth in claim 5 wherein said polylactide-co-glycolide has a weight average molecular weight of from about 20,000 to about 100,000. 7. The method as set forth in claim 5 wherein said polylactide-co-glycolide has a weight average molecular weight of from about 30,000 to about 45,000. 8. The method as set forth in claim 5 wherein said polylactide-co-glycolide contains 45 to 90 mole percent of lactide and 10 to 55 mole percent of glycolide units respectively. 9. The method as set forth in claim 1 wherein said mixing in step (a) is carried out at ambient temperature. 10. The method as set forth in claim 1 wherein said mixing in step (a) is carried out at a temperature in the range of from about 20 degree C to about 30 degree C. 11. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out using an extruder. 12. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out using a single screw extruder. 13. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out using a twin screw extruder. 14. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out at a temperature in the range of from about 60 degree C to about 140 degree C. 15. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out at a temperature in the range of from about 80 degree C to about 120 degree C. 16. The method as set forth in claim 1 wherein said shear mixing in step (b) is carried out at a temperature in the range of from about 95 degree C to about 115 degree C. 17. The method as set forth in claim 1 wherein weight ratio of said pharmaceutically active molecule to said polymer is in the range of from about 5:95 to about 25:75. 18. The method as set forth in claim 1 wherein weight ratio of said pharmaceutically active molecule to said polymer is in the range of from about 10:90 to about 20:80. 19. The method as set forth in claim 1 wherein said pharmaceutically active molecule is dissolved in said polymer at least to an extent of about 50 weight percent based on the total weight of said pharmaceutically active molecule present in said composition. 20. The method as set forth in claim 1 wherein said pharmaceutically active molecule is dissolved in said polymer at least to an extent of about 90 weight percent based on the total weight of said pharmaceutically active molecule present in said composition. 21. The method as set forth in claim 1 wherein said microparticles are added to a pharmaceutically acceptable solution to form an injectable suspension. 22. The method as set forth in claim 21 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of at least about 2 weeks at a dose sufficient to antagonize the effects of serotonin at the 5HT2A receptor. 23. The method as set forth in claim 21 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of from about 2 weeks to about one month at a dose sufficient to antagonize the effects of serotonin at the 5HT2A receptor. 24. A method for the preparation of a pharmaceutical composition comprising the steps of: a) mixing a pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof and a polylactide-co-glycolide polymer at a temperature of about 25 degree C and atmospheric pressure conditions for a sufficient period of time to form a mixture of said compound and said polymer, wherein weight ratio of said compound to said polymer is in the range of from about 10:90 to about 15:85, and wherein said polymer has a glass transition temperature (Tc) of less than about 60 degree C.; b) drying said mixture under vacuum at a temperature of about 25 degree C for a sufficient period of time such that moisture content of said mixture is less than about 0.02 weight percent; c) passing said dry mixture through a heated twin screw extruder having at least one left handed element at a sufficient shear rate and at temperature of from about 95 degree C to 115 degree C for a sufficient period of time such that said polymer is allowed to soften to form a fluidized medium and said compound is allowed to substantially dissolve in said polymer to form a solid solution having a substantially homogeneously dispersed mixture of said compound in said polymer matrix and extruding said homogeneous mixture into a strand, wherein said shearing conditions are maintained in such a way that less than one weight percent of said compound reacts with said polymer; d) pelletizing said strand; and e) pulverizing and sieving said pellets to form injectable microparticles having a size distribution in the range of from about 10 to 100 mkm of the pharmaceutical composition. 25. A pharmaceutical composition consisting essentially of: microparticles having a size distribution in the range so from about 10 to 100 mkm formed of: a) a biodegradable polymer in an amount of about 80 to 95 percent by weight, wherein said polymer has a glass transition temperature (Tg) of less than about 60 degree C; and b) a pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 5 to 20 percent by weight; wherein said compound is dissolved and uniformly dispersed in polymer. 26. The composition as set forth in claim 25 wherein said compound is a 5HT2A receptor antagonist. 27. The composition as set forth in claim 25 wherein said polymer is polylactide-co-glycolide. 28. The composition as set forth in claim 25 wherein said polylactide-co-glycolide has a weight average molecular weight of from about 20,000 to about 100,000. 29. The composition as set forth in claim 25 wherein said polylactide-co-glycolide has a weight average molecular weight of from about 30,000 to about 45,000. 30. The composition as set forth in claim 25 wherein said polylactide-co-glycolide contains 45 to 90 mole percent of lactide and 10 to 55 mole percent of glycolide units respectively. 31. The composition as set forth in claim 25 wherein said pharmaceutically active molecule is dissolved in said polymer at least to an extent of about 50 weight percent based on the total weight of said pharmaceutically active molecule present in said composition. 32. The composition as set forth in claim 25 wherein said pharmaceutically active molecule is dissolved in said polymer at least to an extent of about 90 weight percent based on the total weight of said pharmaceutically active molecule present in said composition. 33. The composition as set forth in claim 25 wherein said microparticles are added to a pharmaceutically acceptable solution to form an injectable suspension. 34. The composition as set forth in claim 33 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of at least about 2 weeks at a dose sufficient to antagonize the effects of serotonin at the 5HT2A receptor. 35. The composition as set forth in claim 33 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of from about 2 weeks to about one month at a dose sufficient to antagonize the effects of serotonin at the 5HT2A receptor. 36. A pharmaceutical composition according to claim 25 useful for antagonizing the effects of serotonin receptor. 37. A pharmaceutical composition according to claim 36 wherein said effects of serotonin receptor are antagonized for a period from about 2 weeks to about one month. 38. A pharmaceutical composition according to claim 25 useful for antagonizing the effects of serotonin at the 5HT2A receptor. 39. A pharmaceutical composition according to claim 38 wherein said effects of serotonin at the are antagonized for a period from about 2 weeks to about one month. 40. A pharmaceutical compositio